The theme of our Program Project, "Cellular Cofactors, Neuronal Stress & Rescue, Aging & AD" is that during aging, the neuronal response to endogenous and exogenous environmental stress undergoes continuous modulation, and that specific cofactors may exert their effects in the central and peripheral nervous systems, modifying the host response. Such modulation may lead to either chronic cellular injury, or to restoration of homeostasis. Our program focuses on two such cofactors, A( binding alcohol dehydrogenase (ABAD), and Receptor for AGE (RAGE), the latter the focus of projects l&2. RAGE is a cell surface interaction site for A( and is expressed by neurons, microglia, and vascular cells. We hypothesized that A( engagement of RAGE propagates chronic cellular activation within the central nervous system (CNS) with injurious outcome (Project 1); ongoing studies in project 1 support this premise. In contrast, in the peripheral nervous system (PNS), RAGE has homeostatic properties, such as serving as a receptor for S 100/calgranulins and amphoterins. These factors are rapidly synthesized and/or released at sites of peripheral nerve injury. We speculate that upon their binding to RAGE, also upregulated in the PNS in response to cellular perturbation, this axis contributes to transient inflammatory and subsequent neuronal reparative processes critical for regeneration. To dissect the role of RAGE in peripheral nerve injury in adult and aging mice, we proposed utilizing RAGE-dependent transgenic (Tg) models with targeted expression of a dominant-negative (DN) RAGE transgene, a form of the receptor lacking the cytosolic tail which blocks RAGE signaling, in wild-type RAGE expressing cells within injured peripheral nerve, mononuclear phagocytes (MPs, macrophage scavenger receptor promoter; MSR) and/or peripheral neurons, (thy-1 promoter). However, as indicated by the members of the Scientific Review Group, the lack of sufficient preliminary expression and functional data in the transgenic DN-RAGE expressing mice limited funding to the first three years, pending re-evaluation. In response, we have characterized these two groups of transgenic mice and established that MP and dorsal root ganglia (DRG) neurons prepared from these animals display strikingly reduced activation upon exposure to RAGE ligands. In vivo, upon sciatic nerve crush, Tg MSR DN RAGE and Tg thy-1 DN RAGE mice display reduced functional recovery after injury and decreased myelinated fiber density compared to littermates. These data support the feasibility of our project; we thus propose to complete the outlined studies to test the role of RAGE in peripheral nerve repair. [unreadable] [unreadable]